The present invention relates to methods for diagnosing visuospatial disorientation or assessing visuospatial orientation capacity and their use in diagnosing neurodegenerative diseases. The present invention also relates to a method for enhancing visuospatial orientation in a subject.
Visuospatial disorientation is the inability to perceive, recall, or navigate through the structured environment surrounding, the individual. It includes topographagnosia (the failure to recognize environmental structure) (Holmes, xe2x80x9cDisturbances of Vision by Cerebral Lesions,xe2x80x9d British J. of Ophthalmology, 2:353-384 (1918); Brain, xe2x80x9cVisual Disorientation With Special Reference to Lesions of the Right Cerebral Hemisphere,xe2x80x9d Brain, 64:244-272 (1941); Critchley, The Parietal Lobes, New York, Hafner Publishing Co. (1953)) and is thought to rely on dorsal stream occipito-parietal visual pathways (Mountcastle et al., The Mindful Brain: Cortical Organization and the Group-Selective Theory of Higher Brain Function, Cambridge, Mass., MIT Press (1978); Ungerleider et al., xe2x80x9cTwo Cortical Visual Systems,xe2x80x9d In: Analysis of Visual Behavior, Ingle et al., eds., Cambridge, MIT Press, pp. 549-586 (1982)).
Damage to parieto-occipital cortex has long been associated with the syndrome of visuospatial disorientation (Holmes, xe2x80x9cDisturbances of Vision By Cerebral Lesions,xe2x80x9d British Journal of Ophthalmology, 2:353-384(1918), Critchley, xe2x80x9cThe Parietal Lobes,xe2x80x9d New York, Hafner Publishing Co., (1953)). More recently, this syndrome has been recognized as a common component of behavioral impairment in Alzheimer""s disease (xe2x80x9cADxe2x80x9d) (Cogan, xe2x80x9cVisual Disturbances With Focal Progressive Dementing Disease,xe2x80x9d American Journal of Ophthalmology, 100:68-72 (1985), Levine et al., xe2x80x9cThe Visual Variant of Alzheimer""s Disease: A Clinicopathologic Case Study,xe2x80x9d Neurology, 305-313 (1993)). AD patients with prominent visuospatial disorientation show neuropathological evidence of greater disease impact on parieto-occipital areas (Hof et al., xe2x80x9cBalint""s Syndrome in Alzheimer""s Disease: Specific Disruption of the Occipito-Parietal Visual Pathway,xe2x80x9d Brain Research, 493:368-375 (1989), Hof et al., xe2x80x9cQuantitative Analysis of a Vulnerable Subset of Pyramidal Neurons in Alzheimer""s Disease: II. Primary and Secondary Visual Cortex,xe2x80x9d The Journal of Comparative Neurology, 301:55-64 (1990)). In addition, functional imaging studies have linked the visuospatial disorientation of AD to metabolic changes in parieto-occipital cortex (Kiyosawa et al., xe2x80x9cAlzheimer""s Disease with Prominent Visual Symptoms Clinical and Metabolic Evaluation,xe2x80x9d Ophthalmology, 96:1077-1086 (1989), Pietrini et al., xe2x80x9cA Longitudinal Positron Emission Tomography Study of Cerebral Glucose Metabolism in Patients With Alzheimer""s Disease and Prominent Visual Impairment,xe2x80x9d Advances in the Biosciences, 87:69-71 (1993)).
Visuospatial disorientation can occur either as an isolated syndrome in a distinct presentation of AD (Cogan, xe2x80x9cVisual Disturbances With Focal Progressive Dementing Disease,xe2x80x9d American J. of Ophthalmology, 11:68-72 (1985)), or with other impairments in the context of typical AD (Becker et al., xe2x80x9cNeuropsychological Function In Alzheimer""s Disease. Pattern of Impairment and Rates of Progression,xe2x80x9d Arch. Neurology, 45:263-268 (1988); Levine et al., xe2x80x9cThe Visual Variant of Alzheimer""s Disease: A Clinicopathologic Case Study,xe2x80x9d Neurology, 43:305-313 (1993)). While some normal elderly subjects show aspects of visuospatial disorientation (Flicker et al., xe2x80x9cEquivalent Spatial-Rotation Deficits in Normal Aging and Alzheimer""s Disease,xe2x80x9d J. of Clinical and Exp. Neuropsychology, 10:294-300 (1988); Lipman et al., xe2x80x9cAdult Age Differences in Memory Routes: Effects of Instruction and Spatial Diagram,xe2x80x9d Psychology and Aging, 7:434-442 (1992)), it is a robust finding in 39% of patients with AD (Henderson et al., xe2x80x9cSpatial Disorientation in Alzheimer""s Disease,xe2x80x9d Arch. Neurol., 46:391-394 (1989)) who often first complain of spatial confusion and at autopsy have posterior cortical atrophy (PCA) (Benson et al., xe2x80x9cPosterior Cortical Atrophy,xe2x80x9d Arch. Neurol., 45:789-793 (1988)). Convincing evidence of this disorder comes from studies of patients with visuospatial disorientation but no memory impairment, who later develop typical AD (Kaskie et al., xe2x80x9cVisuospatial Deficit in Dementia of the Alzheimer Type,xe2x80x9d Arch. Neurol., 52:422-425 (1995); Butter et al., xe2x80x9cVisual-Spatial Deficits Explain Visual Symptoms in Alzheimer""s Disease,xe2x80x9d Am. J. Ophthalmology, 122:97-105 (1996)). These patients can be contrasted to AD without visual complaints and verbal, but not spatial, impairments (Binetti et al., xe2x80x9cDisorders of Visual and Spatial Perception of the Early Stage of Alzheimer""s Disease,xe2x80x9d Annals of the NY Academy of Sciences, 777:221-225 (1996)).
Visuospatial AD must be distinguished from primary visual dysfunction in the setting of AD. AD associated losses of visual acuity, contrast sensitivity, and visual fields are associated with optic atrophy with abnormal visual evoked potentials (VEPs) (Sadun et al., xe2x80x9cAssessment of Visual Impairment in Patients With Alzheimer""s Disease,xe2x80x9d Am. J. of Ophthalmology, 104:113-120 (1987)). But many AD patients with prominent visual complaints have normal electroretinograms (ERGs) and VEPs (Rizzo et al., xe2x80x9cA Human Visual Disorder Resembling Area V4 Dysfunction in the Monkey,xe2x80x9d Neurology, 42:1175-1180 (1992)) and profiles of visual impairment that suggest dysfunction in visual association cortex (Cronin-Golomb et al., xe2x80x9cVisual Dysfunction in Alzheimer""s Disease Relation to Normal Aging,xe2x80x9d Annals of Neurology, 29:41-52 (1991)). These patients have visuospatial impairments, in the absence of verbal-memory impairments, and fit the neuropsychological profile of posterior cerebral involvement with the preservation of other areas (Furey-Kurkjian et al., xe2x80x9cVisual Variant of Alzheimer""s Disease: Distinctive Neuropsychological Features,xe2x80x9d Neuropsychology, 10:294-300 (1996)).
The histopathology of AD is most evident in limbic areas, but the greatest cortical involvement is in parietotemporal association areas (Brun et al., xe2x80x9cDistribution of Cerebral Degeneration in Alzheimer""s Disease,xe2x80x9d Arch. Psychiat. Nervenkr., 223:15-33 (1976); Brun et al., xe2x80x9cRegion Pattern of Degeneration in Alzheimer""s Disease: Neuronal Loss and Histopathological Grading,xe2x80x9d Histopathology, 5:549-564 (1981); Mountjoy et al., xe2x80x9cCortical Neuronal Counts in Normal Elderly Controls and Demented Patients,xe2x80x9d Neurobiology of Aging, 4:1-11 (1983)) with neurofibrillary tangles (NFTs) increasing from primary to tertiary visual areas especially effecting corticocortical projection neurons (Lewis et al., xe2x80x9cLaminar and Regional Distributions of Neurofibrillary Tangles and Neuritic Plaques in Alzheimer""s Disease: A Quantitative Study of Visual and Auditory Cortices,xe2x80x9d The Journal of Neuroscience, 7:1799-1808 (1987); Arnold et al., xe2x80x9cThe Topographical and Neuroanatomical Distribution of Neurofibrillary Tangles and Neuritic Plaques in the Cerebral Cortex of Patients With Alzheimer""s Disease,xe2x80x9d 1:103-116 (1991)). In visual AD the pathology is more concentrated in visual areas (Hof et al., xe2x80x9cBalint""s Syndrome in Alzheimer""s Disease: Specific Disruption of the Occipito-Parietal Visual Pathway,xe2x80x9d Brain Research, 493 :368-375 (1989); Hof et al., xe2x80x9cQuantitative Analysis of a Vulnerable Subset of Pyramidal Neurons in Alzheimer""s Disease: II. Primary and Secondary Visual Cortex,xe2x80x9d The Journal of Comparative Neurology, 301:55-64 (1990)), especially in neurons with intracortical projections to visual association areas, potentially creating a functional disconnection in the occipito-parietal visual pathway (Hof et al., xe2x80x9cQuantitative Analysis of a Vulnerable Subset of Pyramidal Neurons in Alzheimer""s Disease: II. Primary and Secondary Visual Cortex,xe2x80x9d The Journal of Comparative Neurology, 301:55-64 (1990)). This posterior cortical localization is confirmed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) studies showing a 35-40% decrease in occipito-parietal blood flow relative to AD patients without visual symptoms (Kiyosawa et al., xe2x80x9cAlzheimer""s Disease With Prominent Visual Symptoms. Clinical and Metabolic Evaluation,xe2x80x9d Ophthalmology, 96:1077-1086 (1989)) with preserved flow in the frontal cortical areas most commonly effected in AD (Pietrini et al. xe2x80x9cA Longitudinal Position Emission Tomography Study of Cerebral Glucose Metabolism in Patients With Alzheimer""s Disease and Prominent Visual Impairment,xe2x80x9d Advances in the Biosciences, 87:69-71 (1993); Pietrini et al., xe2x80x9cPreferential Metabolic of Visual Cortical Areas in a Subtype of Alzheimer""s Disease: Clinical Implications,xe2x80x9d American Journal of Psychiatry, 153:1261-1268 (1996)).
Normal elderly and AD subjects show impaired visual motion detection with thresholds substantially higher than those of young normals (Mendola et al., xe2x80x9cPrevalence of Visual Deficits in Alzheimer""s Disease,xe2x80x9d Optometry and Vision Science, 72:155-167 (1995)). Discrimination thresholds for the direction of visual motion also increase with age, doubling from age 30 to 80 years, with dramatic increases in patients with AD (Trick et al., xe2x80x9cVisual Sensitivity of Motion: Age-Related Changes and Deficits in Senile Dementia of the Alzheimer Type,xe2x80x9d Neurology, 41:1437-1440 (1991)). Gilmore (Gilmore et al., xe2x80x9cMotion Perception and Alzheimer""s Disease,xe2x80x9d Journal of Gerontology, 49:P52-7 (1994)) found a strong correlation between visual motion thresholds and cognitive impairments in AD and evidence of a relationship between visual motion thresholds and visuospatial impairments (Gilmore et al., xe2x80x9cMotion Perception and Aging.xe2x80x9d Psychology and Aging, 7:654-600 (1992)).
These findings demand consideration of the possibility that visual motion impairments in aging and AD might reflect an ocular visual disorder which blocks central access to visual motion signals. This issue has been clarified by studies of the multiple visual impairments of AD (Cronin-Golomb et al., xe2x80x9cVisual Dysfunction Alzheimer""s Disease Relation to Normal Aging,xe2x80x9d Annals of Neurology, 29:41-52 (1991)) showing that object recognition deficits are accounted for by losses in acuity, color discrimination, contract sensitivity, etc., but visuospatial deficits can not be so explained (Cronin-Golomb et al., xe2x80x9cVisual Dysfunction Predicts Cognitive Deficits in Alzheimer""s Disease,xe2x80x9d Optometry and Vision Science, 72:168-176 (1995)). The cortical origin of the visual motion detection deficit in AD is supported by data showing that they have impaired visual motion perception, but normal motion thresholds for inducing optokinetic nystagmus (Silverman et al., xe2x80x9cDissociation Between the Detection and Perception of Motion in Alzheimer""s Disease,xe2x80x9d Neurology, 44:1814-1818 (1994)).
Functional imaging has identified the human visual motion cortex, and suggested that the visuospatial disorientation of AD is attributable to a disorder in this system. Visual motion activation in normal humans has been localized to the inferior parietal and superior temporal gyri of occipito-parietal cortex using H215O-PET (Dupont et al., xe2x80x9cMany Areas in the Human Brain Respond to Visual Motion,xe2x80x9d Journal of Neurophysiology, 72:1420-1424 (1994); de Jong et al., xe2x80x9cThe Cerebral Activity Related to the Visual Perception of Forward Motion in Depth,xe2x80x9d Brain, 117:1039-1054 (1994); Cheng et al., xe2x80x9cHuman Cortical Regions Activated By Wide-Field Visual Motion: An H215O-PET Study,xe2x80x9d Journal of Neurophysiology, 74:413-427 (1995) (Abstract)) and functional magnetic resonance imaging (fMRI). This region is activated in visuospatial perception tasks studied by PET (Haxby et al., xe2x80x9cThe Functional Organization of Human Extrastriate Cortex: A PET-rCBF Study of Selective Attention to Faces and Locations,xe2x80x9d The Journal of Neurosciences, 14:6336-6353 (1994)) and fMRI (Aguirre et al., Environmental Knowledge is Subserved by Separable Dorsal/Ventral Neural Areas,xe2x80x9d The Journal of Neuroscience, 17:2512-2518 (1997)), with visual AD subjects showing impaired activation of these occipito-parietal areas during visual motion processing (Mentis et al., xe2x80x9cVisual Cortical Dysfunction in Alzheimer""s Disease Evaluated With a Temporally Graded xe2x80x9cStress Testxe2x80x9d During PET,xe2x80x9d Am. J. Psychiatry, 153:32-40 (1996)). However, PET studies also show that when spatial memory is engaged, a critical aspect of spatial behavior in the elderly (Simon et al., xe2x80x9cSpatial Cognition and Neighborhood Use: The Relationship in Older Adults,xe2x80x9d Psychology and Aging, 7:389-394 (1992)), there is also hippocampal and parahippocampal activation (Aguirre et al., xe2x80x9cThe Parahippocampus Subserves Topographical Learning in Man,xe2x80x9d Cerebral Cortex, 6:823-829 (1996)). Thus, PET studies show the complexities of spatial behavior, not contradicting the hypothesized role of visual motion processing, but reminding us that hippocampal memory of a cognitive map (O""Keefe et al., The Hippocampus as a Cognitive Map, Clarendon, Oxford (1978)) is another element of spatial orientation that might be susceptible to impairment in AD.
Gibson (Gibson, The Perception of the Visual World, Boston, Houghton Mifflin (1950); Optical Motions and Transformations as Stimuli for Visual Perception,xe2x80x9d Psychological Review, 64:288-295 (1957)) first emphasized that spatial orientation relies on the processing of the patterned visual motion of optic flow which surrounds a moving observer, and is accompanied by the visual motion of discrete objects, as cues about self-movement and the three-dimensional structure of the environment. Subsequently, others have used geometric and computational analyses to confirm that visual motion is a rich source of information about observer movement through extrapersonal space (Lee, xe2x80x9cThe Optic Flow Field: The Foundation of Vision.xe2x80x9d Philosophical Transactions of the Royal Society of Londonxe2x80x94Series B: Biological Sciences, 290:169-179 (1980); Heeger, xe2x80x9cModel for the Extraction of Image Flow,xe2x80x9d J. Opt. Soc. Am. A., 4:1455-1471 (1987); Perrone, xe2x80x9cA Simple Technique For Optical Flow Estimation,xe2x80x9d J. Opt. Soc. Am. A., 7:264-278. (1990); Fermuller et al., xe2x80x9cDirect Perception of Three-Dimensional Motion From Patterns of Visual Motion,xe2x80x9d Science, 270:1973-1976 (1995)) and the three-dimensional structure of the visual environment (Koenderink et al., xe2x80x9cInvariant Properties of the Motion Parallax Field Due to the Movement of Rigid Bodies Relative to an Observer,xe2x80x9d Optica Acta, 22:773-791 (1975); Rogers et al., xe2x80x9cMotion Parallax as an Independent Cue for Depth Perception,xe2x80x9d Perception, 8:125-134 (1979); Braunstein et al., xe2x80x9cShape and Depth Perception From Parallel Projections of Three-Dimensional Motion,xe2x80x9d J. Exp. Psych., 10:749-760 (1984); Simpson, xe2x80x9cOptic Flow and Depth Perception,xe2x80x9d Spatial Vision, 7:35-75 (1993)).
Psychophysical analyses of human performance have shown that visual motion cues are accessed in tests of self-movement perception (Warren et al., xe2x80x9cDirection of Self-Motion is Perceived From Optical Flow,xe2x80x9d Nature, 336:162-163 (1988); Banks et al., xe2x80x9cEstimating Heading During Real and Simulated Eye Movements,xe2x80x9d Vision Research, 36:431-443 (1996); Stone et al., xe2x80x9cHuman Heading Estimation During Visually Simulated Curvilinear Motion,xe2x80x9d Vision Research, 37:573-590 (1997)), although the exact nature of the underlying perceptual strategies remains a subject of intense scrutiny (Rieger et al., xe2x80x9cProcessing Differential Image Motion,xe2x80x9d J. Opt. Soc. Am. A., 2:354-359 (1985); Stone et al., xe2x80x9cHuman Heading Perception Cannot Be Explained Using a Local Differential Motion Algorithm,xe2x80x9d Invest. Oplhthalmol. Vis. Sci., 34:1229 (1993); Lappe et al., xe2x80x9cNeural Network for the Processing of Optic Flow From Ego-Motion in Higher Mammals,xe2x80x9d Neural Computation, 5:374-391 (1993)). Visual motion has also been shown to cue observers about the layout of the visual environment (Lee, xe2x80x9cA Theory of Visual Control of Braking Based on Information About Time-To-Collision,xe2x80x9d Perception, 5:437-459 (1976); Cornilleau-Peres et al., xe2x80x9cStereo-Motion Cooperation and the Use of Motion Disparity in the Visual Perception of 3-D Structure,xe2x80x9d Perception and Psychophysics, 54:223-239 (1993); Regan et al., xe2x80x9cVisual Processing of Looming and Time to Contact Throughout the Visual Field,xe2x80x9d Vision Research, 35:1845-1857 (1995)), to guide locomotion (Lee, xe2x80x9cA Theory of Visual Control of Braking Based on Information About Time-To-Collision,xe2x80x9d Perception, 5:437-459 (1976); Lee et al., xe2x80x9cVisual Control of Locomotion,xe2x80x9d Scand. J. Psychol., 18:224-230 (1977)), and reaching (Lee et al., xe2x80x9cVisual Timing of Interceptive Behavior,xe2x80x9d In: Brain Mechanisms and Spatial Vision, lugle et al., eds., Dordrecht, The Netherlands Martins Nijhoff (1985); Savelsbergh et al., xe2x80x9cThe Visual Guidance of Catching,xe2x80x9d Exp. Brain Res., 93:148-156 (1993)). Furthermore, visual motion can have so profound an effect on orienting mechanisms that a variety of illusions of self-movement and spatial disorientation can be triggered by visual motion stimuli (Held et al., xe2x80x9cCharacteristics of Moving Visual Scenes Influencing Spatial Orientation,xe2x80x9d Vision Res., 15:357-364 (1975); Berthoz et al., xe2x80x9cPerception of Linear Horizontal Self-Motion Induced by Peripheral Vision (Linearvection) Basic Characteristics and Visual-Vestibular Interactions,xe2x80x9d Experimental Brain Research, 23:471-489 (1975); Ohmi et al., xe2x80x9cCircular Vection as a Function of Foreground-Background Relationships,xe2x80x9d Perception, 16:17-22 (1987)).
Neurophysiologic studies have demonstrated that primate visual cortex neurons encode the large visual motion patterns of optic flow (Saito et al., xe2x80x9cIntegoration of Direction Signals of Image Motion in the Superior Temporal Sulcus of the Macaque Monkey,xe2x80x9d Journal of Neuroscience, 6:145-157 (1986); Tanaka et al., xe2x80x9cUnderlying Mechanisms of the Response Specificity of Expansion/Contraction and Rotation Cells in the Dorsal Part of the Medial Superior Temporal Area of the Macaque Monkey,xe2x80x9d J. Neurophysiol., 62:642-656 (1989); Duffy et al., xe2x80x9cSensitivity of MST Neurons to Optic Flow Stimuli. I. A Continuum of Response Selectivity to Large-Field Stimuli,xe2x80x9d J. Neurophysiol., 65:1329-1345 (1991); Duffy et al., xe2x80x9cSensitivity of MST Neurons to Optic Flow Stimuli. II. Mechanisms of Response Selectivity Revealed By Small-Field Stimuli.xe2x80x9d J. Neurophysiol., 65:1346-1359 (1991); Orban et al., xe2x80x9cFirst-Order Analysis of Optical Flow in Monkey Brain,xe2x80x9d Proceedings of the National Academy of Sciences of the United States of America, 89:2595-2599 (1992); Graziano et al., xe2x80x9cTuning of MST Neurons to Spiral Motion,xe2x80x9d J. Neurosci., 14:54-67 (1994)) responding to the direction of self-movement and the environmental layout (Duffy et al., xe2x80x9cResponse of Monkey MST Neurons to Optic Flow Stimuli With Shifted Centers of Motion,xe2x80x9d J. Neurosci., 15:5192-5208 (1995); Duffy et al., xe2x80x9cPlanar Directional Contributions to Optic Flow Responses in MST Neurons,xe2x80x9d J. Neurophysiol., 77:782-796 (1997); Duffy et al., xe2x80x9cMedial Superior Temporal Area Neurons Respond to Speed Patterns in Optic Flow,xe2x80x9d J. Neurosci., 17:2839-2851 (1997)) while integrating visual and vestibular signals about orientation (Duffy, xe2x80x9cReal Movement Responses of Optic Flow Neurons in MST,xe2x80x9d Society for Neuroscience Abstracts, 22:1692 (1996) (Abstract)). Neuronal mechanisms for the analysis of visual object motion have shown selective responses to movement along a specific trajectory (Motter et al., xe2x80x9cFunctional Properties of Parietal Visual Neurons: Mechanisms of Directionality Along a Single Axis,xe2x80x9d J. Neurosci., 7:154-176 (1987); Steinmetz et al., xe2x80x9cFunction Properties of Parietal Visual Neurons: Radial Organization of Directionalities Within the Visual Field,xe2x80x9d J. Neurosci., 7:177-191 (1987)) of relative object motion (Tanaka et al., xe2x80x9cAnalysis of Object Motion in the Ventral Part of the Medial Superior Temporal Area of the Macaque Visual Cortex,xe2x80x9d J. Neurophysiol., 69:128-142 (1993)) regardless of the specific form of the object (Geesaman et al., xe2x80x9cThe Analysis of Complex Motion Patterns By Form/Cue Invariant MSTd Neurons,xe2x80x9d J. Neurosci., 16:4716-4732 (1996)) even when embedded in conflicting patterns of optic flow (Logan et al., xe2x80x9cMST Neurons Integrate Visual Cues From Self- and Object-Motion.xe2x80x9d Soc. Neurosci. Abstr., 23:1126 (1997) (Abstract)). These neurons might interact with cortical representations of head direction (Chen et al., xe2x80x9cHead Direction Cells in Rat Posterior Cortex. I. Anatomical Distribution and Behavioral Modulation,xe2x80x9d Exp. Brain Res., 101:8-23 (1994); Chen et al., Head Direction Cells in Rat Posterior Cortex. II. Contributions of Visual and Ideothetic Information to the Directional Firing,xe2x80x9d Exp. Brain Res., 101:23-34 (1994)) and body rotation (McNaughton et al., xe2x80x9cCortical Representation of During Unrestrained Spatial Navigation in the Rat,xe2x80x9d Cerebral Cortex, 4:27-39 (1994)) to create a neural signal driving memory mechanisms for spatial orientation (O""Keefe et al., The Hippocampus as a Cognitive Map, Clarendon, Oxford (1978)) which rely on place sensitive hippocampal neurons for spatial memory (Bostock et al., xe2x80x9cExperience-Dependent Modifications of Hippocampal Place Cell Firing,xe2x80x9d Hippocampus, 1:193-206 (1991); Sharp et al., xe2x80x9cInfluences of Vestibular and Visual Motion Information on the Spatial Firing Patterns of Hippocampal Place Cells,xe2x80x9d J. Neurosci., 15:173-189 (1995)) to create an internal map of extrapersonal space in the context of relevant visuospatial cues (Mueller et al., xe2x80x9cVisually Induced Vertical Self-Motion Sensation is Altered in Microgravity Adaptation,xe2x80x9d J. Vestibular Research, 4:161-167 (1994); Gothard et al., xe2x80x9cDynamics of Mismatch Correction in the Hippocampal Ensemble Code for Space: Interaction Between Path Integration and Environmental Cues,xe2x80x9d J. Neurosci., 60:8027-8040 (1996); O""Keefe et al., xe2x80x9cGeometric Determinants of the Place Fields of Hippocampal Neurons,xe2x80x9d Nature, 381:425-428 (1996)).
Single neuron recordings in the dorsal extrastriate visual cortex of monkeys have shown selective responses to the visual motion patterns of optic flow (Tanaka et al., xe2x80x9cUnderlying Mechainisms of the Response Specificity of Expansion/Contraction and Rotation Cells in the Dorsal Part of the Medial Superior Temporal Area of the Macaque Monkey,xe2x80x9d J. Neurophysiol, 62:642-656 (1989), Duffy et al., xe2x80x9cSensitivity of MST Neurons to Optic Flow Stimuli. II. Mechanisms of Response Selectivity Revealed by Small-Field Stimuli.xe2x80x9d Journal of Neurophysiology, 65:1346-1359 (1991)). Neurons in these areas are activated by visual cues about heading direction (Duffy et al., xe2x80x9cResponse of Monkey MST Neurons to Optic Flow Stimuli With Shifted Centers of Motion,xe2x80x9d Journal of Neuroscience, 15:5192-5208 (1995)) and environmental structure (Duffy et al., xe2x80x9cMedial Superior Temporal Area Neurons Respond to Speed Patterns in Optic Flow,xe2x80x9d Journal of Neuroscience, 17:2839-2851 (1997)) that are embedded in the optic flow field. These dorsal extrastriate areas of monkey cerebral cortex are homologous to parts of human parieto-occipital cortex (Haxby et al., xe2x80x9cThe Functional Organization of Human Extrastriate Cortex: A PET-rCBF Study of Selective Attention to Faces and Locations,xe2x80x9d The Journal of Neurosciences, 14:6336-6353(1994), Sereno et al., xe2x80x9cBorders of Multiple Visual Areas in Humans Revealed by Functional magnetic Resonance imaging,xe2x80x9d Science, 268:889-893 (1995)) containing multiple centers for visual motion processing (Dupont et al., xe2x80x9cMany Areas in the Human Brain Respond to Visual Motion,xe2x80x9d Journal of Neurophysiology, 72:1420-1424 (1994), de Jong et al., xe2x80x9cThe Cerebral Activity Related to the Visual Perception of Forward Motion in Depth, Brain, 117:1039-1054 (1994)).
Gibson first emphasized that the visual motion in optic flow influences postural control (Gibson, xe2x80x9cThe Perception of the Visual World,xe2x80x9d Boston, Houghton Mifflin (1950)). Early studies integrating the posturography with optic flow stimuli demonstrated visuo-postural reflexes elicited by visual motion in the central visual field (Brandt et al., xe2x80x9cDifferential Effects of Central Versus Peripheral Vision on Egocentric and Exocentric Motion Perception,xe2x80x9d Exp. Brain Res., 16:476-491 (1973), Lee, xe2x80x9cThe Optic Flow Field: The Foundation of Vision,xe2x80x9d Philosophical Transactions of the Royal Society of Londonxe2x80x94Series B: Biological Sciences, 290:169-179 (1980); Lestienne et al., xe2x80x9cPostural Readjustments Induced by linear Motion of Visual Scenes,xe2x80x9d Exp. Brain Res., 28:363-384 (1977)). More recent work has explored the visual stimulus parameters that influence the direction, amplitude, and temporal aspects of visuo-postural responses (Stoffregen, xe2x80x9cThe Role of Optical Velocity in the Control of Stance,xe2x80x9d Perception and Psychophysics, 39:355-360 (1986); Asten et al., xe2x80x9cPostural Adjustments Induced by Simulated Motion of Differently Structured Environments,xe2x80x9d Exp. Brain Res., 73:371-383 (1988); Gielen et al., xe2x80x9cPostural Responses to Simulated Moving Environments are not Invariant for the Direction of Gaze,xe2x80x9d Exp. Brain Res., 79:167-174 (1990)). Previous work on postural control in monkeys has documented optic flow induced responses, potentially under the influence of visual motion processing in cortical area medial superior temporal (xe2x80x9cMSTxe2x80x9d) (Duffy et al., xe2x80x9cOptic Flow, Posture, and the Dorsal Visual Pathway,xe2x80x9d in Perception. Memory, and Emotion: Frontiers in Neuroscience, Ono et al., eds., Elsevier, N.Y., pp. 63-77 (1996)).
Vision increasingly controls postural stability in aging, possibly because of common losses in proprioceptive and vestibular input (Pyykko et al., xe2x80x9cPostural Control in Elderly Subjects,xe2x80x9d Age and Aging, 19:215-221 (1990); Lord et al., xe2x80x9cVisual Field Dependence in Elderly Fallers and Non-fallers,xe2x80x9d Int""l. J. Aging and Human Development, 31:267-277 (1990)) interacting with the normal dominance of vision in the postural control hierarchy (Lee, xe2x80x9cThe Optic Flow Field: The Foundation of Vision,xe2x80x9d Philosophical Transactions of the Royal Society of Londonxe2x80x94Series B: Biological Sciences, 290:169-179 (1980)). This reliance on vision has been related to the risk of falling in the elderly, especially with unstable support surfaces (Maki et al., xe2x80x9cAging and Postural Control: A Comparison of Spontaneous- and Induced-Sway Balance Tests,xe2x80x9d J. Am. Geriatrics Society, 38:1-9 (1990);Whipple et al., Altered Sensory Function and Balance in Older Persons,xe2x80x9d The Journal of Gerontology, 48:71-76 (1993)). Specific conditions that destabilize the elderly have found disorders of sensory integration and motor coordination (Alexander, xe2x80x9cPostural Control in Older Adults,xe2x80x9d J. Am. Geriatrics Society, 42:93-108 (1994); Baloh et al., xe2x80x9cComparison of Static and Dynamic Posturography in Young and Older Normal People,xe2x80x9d J. Am. Geriatrics Society, 42:405-412 (1994)) including forced reliance on the visual motion of optic flow presented in the peripheral visual field (Wade et al., xe2x80x9cOptical Flow, Spatial Orientation, and the Control of Posture in the Elderly,xe2x80x9d J. Gerontology, 50B:P51-P58 (1995)).
Visual stimuli have an exaggerated influence on postural control in patients with Parkinson""s disease (PD) contributing to their freezing in door ways and other visual barriers (Flowers, xe2x80x9cVisual xe2x80x9cClosed-Loopxe2x80x9d and xe2x80x9cOpen-Loopxe2x80x9d Characteristics of Voluntary Movement in Patients with Parkinsonism and Intention Tremor,xe2x80x9d Brain, 99:269-310 (1976); Cooke et al., xe2x80x9cIncreased Dependence on Visual Information for Movement Control in Patients with Parkinson""s Disease,xe2x80x9d Canadian Journal of Neurological Sciences, 5:413-415 (1978)). Optic flow induced postural responses are increased in PD but not in cerebellar extrapyramidal disorders (Bronstein et al., xe2x80x9cVisual Control of Balance in Cerebellar and Parkinsonian Syndromes,xe2x80x9d Brain, 113:767-779 (1990)). This effect does not reflect the loss of peripheral proprioceptive or vestibular input in these patients (Pastor et al., xe2x80x9cVestibular Induced Postural Responses in Parkinson""s Disease,xe2x80x9d Brain, 116:1177-1190 (1993)). In contrast, patients with Alzheimer""s disease (AD) show postural instability only when confronted with unstable support surfaces with fall risks that are not clearly related to scores on a variety of cognitive tests (Alexander et al., xe2x80x9cMaintenance of Balance, Gait Patterns, and Obstacle Clearance in Alzheimer""s Disease,xe2x80x9d Neurology, 45:908-914 (1995)).
A need continues to exist, however, to elucidate the neurobehavioral mechanisms of visuospatial disorientation in aging and neurodegenerative diseases, such as AD. More particularly, a need exists to characterize the contributions of optic flow to visuospatial orientation and, as a result, neurodegenerative diseases. The present invention is directed to overcoming the above-noted deficiencies in the prior art.
The present invention relates to a method for diagnosing visuospatial disorientation or assessing visuospatial orientation capacity in a subject including conducting an optic flow test on the subject, recording results of the optic flow test, and comparing the results of the optic flow test against a threshold for optic flow perception.
The present invention also relates to a method for diagnosing visuospatial disorientation or assessing visuospatial orientation capacity in a subject including conducting an optic flow test on the subject, conducting at least one optic perception and interpretation test other than an optic flow test on the subject, recording results of the optic flow test and the at least one optic perception and interpretation test, making a first comparison of the results of the optic flow test against a threshold for optic flow perception, and making a second comparison of the results of the at least one optic perception and interpretation test against a threshold for the at least one optic perception and interpretation test.
Another aspect of the present invention is a method for diagnosing visuospatial disorientation or assessing visuospatial orientation capacity in a subject including conducting an optic flow test on the subject, measuring brain wave responses to record an evoked potential in response to the optic flow test, and comparing the evoked potential against a threshold for optic flow perception.
The present invention also relates to a method for enhancing visuospatial orientation in a subject which includes presenting optic flow stimuli on a device to provide a sense of self-movement.
The methods of the present invention allow for the early detection of neurobehavioral impairments, such as Alzheimer""s disease. Such early detection is an improvement over the methods of diagnosis in the prior art and allows treatment to be started at an earlier stage of the disease.
In addition, these methods allow the visuospatial orientation capacity of a subject to be assessed for a number of purposes including identifying subjects who will be safe drivers and identifying those with an enhanced visuospatial orientation capacity for employment in certain fields, e.g., pilots.
A further advantage of the present invention is that the visuospatial orientation of a user of a device, such as a heads-up display used by pilots, can be enhanced by simulating movement to allow the user to better perform a job or activity. dr
FIGS. 1A-D show the radial pattern of optic flow as a function of observer movement;
FIGS. 2A-F show visual discrimination stimuli including shape discrimination stimuli (FIGS. 2A-B), horizontal motion stimuli (FIGS. 2C-D), and radial optic flow stimuli (FIGS. 2E-F);
FIGS. 3A-D show shape and optic flow stimuli and results for visual memory tests;
FIGS. 4A-G show optic flow stimuli and results for optic flow remembered heading tests;
FIGS. 5A-D show object displacement stimuli for an object vision test;
FIGS. 6A-B show schematic diagrams of top (FIG. 5A) and side (FIG. 5B) views of a visual orientation laboratory;
FIG. 7 is a graph showing visual discrimination thresholds from the three stimulus sets in the three subject groups;
FIG. 8 is a graph showing profile plots of the relationship between horizontal motion and radial optic flow discrimination thresholds;
FIG. 9 is a scatter plot showing a relationship between radial optic flow threshold (abscissa) and performance on the spatial navigation test (ordinate);
FIGS. 10A-E show studies of the ability to interpret optic flow as simulating self-movement conducted in young normal (YN), elderly normal (EN), and Alzheimer""s subjects who were normal (ADN) or impaired (ADI) by optic flow discrimination testing;
FIGS. 11A-F show the average evoked responses recorded from the scalps of eight young normal subjects in response to 222 presentations of alternating inward and outward radial optic flow patterns; and
FIGS. 12A-D are graphs showing posture tracings from an elderly normal and Lewy Body disease patient (posture here in force plate units).